Gene Validity Classification Summary

Gene/Disease Pair:

MYO15A : nonsyndromic genetic deafness

HGNC:7594 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
12
12
Rehman AU et al. 2016 Oct (PMID:27375115); Bademci G et al. 2016 Apr (PMID:26226137); Schrauwen I et al. 2013 Jan (PMID:23208854); Belguith H et al. 2009 Feb (PMID:19309289);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
1.5
Rehman AU et al. 2016 Oct (PMID:27375115);
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 1
Belyantseva IA et al. 2005 Feb (PMID:15654330);
Expression 0.5 0 - 2 1
Delprat B et al. 2005 Feb 1 (PMID:15590698);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 4
Probst FJ et al. 1998 May 29 (PMID:9603735); Anderson DW et al. 2000 Jul 22 (PMID:10915760);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
2
Probst FJ et al. 1998 May 29 (PMID:9603735);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
08/30/2018
EXPERT CURATION (DATE)
Definitive
08/30/2018
EVIDENCE SUMMARY
The MYO15A gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/6/17. This association was made using case-level data. Twelve variants (missense, nonsense, frameshift and splice-site) were scored for this curation. MYO15A was first associated with this disease in humans as early as 1998 (Wang et al.​). Association is seen in at least 12 probands in 4 publications (27375115, 26226137, 23208854, 19309289), however much more evidence is available in the literature. The maximum score for genetic evidence and experimental evidence has been reached. Rehman et al. 2016 provides a summary of available published MYO15A variants (27375115). This gene-disease association is supported by two mouse models and a mouse rescue (9603735, 10915760). In summary, MYO15A is definitively associated with autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/17.